Design of antiangiogenic hypoxic cell radiosensitizers: 2-Nitroimidazoles containing a 2-aminomethylene-4-cyclopentene-1,3-dione moiety

Abstract

We designed chiral 2-nitroimidazole derivatives containing a 2-aminomethylene-4-cyclopentene-1,3-dione moiety as antiangiogenic hypoxic cell radiosensitizers. Based on results of molecular orbital calculations, the 2-aminomethylene-4-cyclopentene-1,3-dione moiety is expected to show high electrophilicity comparable to that of the 2-methylene-4-cyclopentene-1,3-dione moiety included in TX-1123 and tyrphostin AG17. We evaluated the antiangiogenic and radiosensitizing effects of the new compounds, along with other biological properties including their activities as hypoxic cytotoxicities and protein tyrosine kinase (PTK) inhibitory activities. Among the compounds tested, 5 (TX-2036) proved to be the strongest antiangiogenic hypoxic cell radiosensitizer. All the other chiral 2-nitroimidazole derivatives having 2-aminomethylene-4-cyclopentene-1,3-dione moiety tested were also antiangiogenic hypoxic cell radiosensitizers. The PTK inhibitory activity of 5 (TX-2036) showed this to be a promising and potent EGFR kinase inhibitor, having an IC 50 value of lower than 2 μM. This compound also was an Flt-1 kinase Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. inhibitor having an IC 50 value of lower than 20 μM. Our results show that these chiral 2-nitroimidazole derivatives that contain the 2-amnomethlene-4-cyclopentene-1,3-dione moiety as a potent antiangiogenic pharmacophoric descriptor are promising lead candidates for the development of antiangiogenic hypoxic cell radiosensitizers. NIH Public Access

Design, synthesis, and antibacterial evaluation of new Schiff’s base derivatives bearing nitroimidazole and pyrazole nuclei as potent E. coli FabH inhibitors

“…The metabolism and toxicology of nitroimidazole derivatives, particularly for secnidazole, have been characterized in recent reports [13,14]. Secnidazole (a, 2-dimethyl-5-nitro-1H-imidazole-1-ethanol) is extraordinarily effective in the treatment of giardiasis, amebiasis, and bacterial vaginosis.…”

“…of -N-H), 3025 (ArC-H), 1690 (C=O stretching), 1225 cm -1 (C-O-C ether stretching); 1 H NMR (DMSO-d 6 ) d ppm: 227, 2.35, 2.45 (s, 9H, 3 9 CH 3 ), 5.96 (s, 2H, CH 2 ), 6.96-7.81 (m, 10H, Ar-H), 8.83 (s, 1H, CH=N), 11.22 (s, 1H, NH);13 C NMR (DMSO-d 6 ) (d): 14.28, 21.17, 21.49 (Ar-CH 3 ), 37.94 (CH 2 -CO), 107.16, 117.19, 122.23, 124.50, 128.44, 129.83, 130.47, 132.38, 136.92, 139.47, 143.47 (-CH=N), 149.22, 152.69, 153.58, 157.73 (Ar-C), 176.21 (C=O); Anal. Calcd.…”

Weak Electric Current Treatment to Artificially Enhance Vascular Permeability in Embryonated Chicken Eggs

“…16) Indeed, using embryonated chicken eggs as an alternate model, it was reported that the in vivo activities of antiangiogenic and radiosensitizing agents could successfully be evaluated in eggs inoculated with tumor cells. [17][18][19] The in vivo antioxidative activity of redox nanoparticles was also previously assessed. 20) Based on these findings, we considered that the influence of ET on vascular permeability and leakage of intravenously injected agents from blood vessels could be evaluated using the embryonated chicken eggs having the vascular structure in the CAM.…”

Evaluation of the in vivo antioxidative activity of redox nanoparticles by using a developing chicken egg as an alternative animal model

“…Thus, the in vivo activity reflecting the pharmacokinetics of candidate compounds may be evaluable using this developing chicken egg model [11]. We have already succeeded in evaluating the in vivo activity of an antiangiogenic agent and a radiosensitizing agent by using this model [12][13][14][15].…”